Darifenacin, (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide, a compound having the chemical structure,
is a selective M3 receptor antagonist. Blockade of destructor muscle activity manifests in an increase in urine volume that the bladder can retain, reduction of urination frequency, and decrease in pressure and urgency associated with the urge to urinate, and thereby episodes of incontinence are reduced.
Darifenacin is administered as the hydrobromide salt, (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide, of the structure
and is marketed under the trade name ENABLEX® by Novartis.
U.S. Pat. No. 5,096,890, hereby incorporated by reference, discloses three routes for the synthesis of darifenacin hydrobromide; all of which comprise the cumbersome and hazardous Mitsunobu reaction, described in the following Scheme.
Accordingly, 1-tosyl-3-(R)-pyrrolidinol is reacted with methyl tosylate, and with diethylazodicarboxylate (DEAD), a very dangerous reagent. Typically, the product is contaminated with triphenylphosphine oxide, which is very difficult to separate from the desired product. Moreover, other toxic and hazardous reagents, such as pyridine and NaH, are used in other steps of the synthesis.
The process disclosed in U.S. publication No. 20003/0191176 for the preparation of darifenacin hydrobromide requires the use of BF3, which is a toxic reagent.
Therefore, there is a need in the art for a process for the preparation of darifenacin hydrobromide that does not use toxic and dangerous reagents and that can be performed on an industrial scale. The present invention provides such processes.